Peptides, compounds, compositions and methods for inhibiting SOX9
The present application provides SOX9 inhibitor compounds and compositions and methods of use thereof. In certain aspects, the SOX9 inhibitor is a peptide comprising a portion of the SOX9 dimerization motif. In other aspects, the SOX9 inhibitor is a compound of the general formula I where one A is H and the other is: and the remaining substituents are as defined in the application.
1 . A pharmaceutical composition comprising a SOX9 dimerization inhibitor and a pharmaceutically acceptable diluent, carrier or excipient, wherein the SOX9 inhibitor is:
an inhibitor compound of formula I:
where:
R 1 is NR 7 R 8 , wherein R 7 and R 8 are each independently a straight or branched C 1 to C 6 alkyl, or R 7 and R 8 , together with the N atom to which they are attached, form a heterocyclyl containing one or two heteroatoms selected from N and O, which is optionally substituted with an alkyl;
R 2 is H, a C 1 to C 6 alkyl, a C 1 to C 6 alkoxy, or halo; and
one A is H and the other is:
where:
R 3 is H or a C 2 to C 6 alkyl;
R 4 is H or a C 1 to C 6 alkyl;
R 5 is H, halo or NCH 2 C 6 H 5 ;
R 6 is H or methyl; and
Y is O or SO 2 ,
or a pharmaceutically acceptable salt or solvate thereof.
2 . The pharmaceutical composition of claim 1 , wherein the SOX9 dimerization inhibitor is the inhibitor compound of formula I and wherein R 1 is piperazine, N-methylpiperazine, morpholine, piperidine, pyrrolidine or N(C 1 -C 6 alkyl) 2 .
3 . The pharmaceutical composition of claim 1 , wherein R 2 is H, methyl, methoxy or Cl.
4 . The pharmaceutical composition of claim 1 , wherein R 3 is H or isopropyl.
5 . The pharmaceutical composition of claim 1 , wherein R 4 is H or methyl.
6 . The pharmaceutical composition of claim 1 , wherein R 5 is H, C 1 or NCH 2 C 6 H 5 .
7 . The pharmaceutical composition of claim 1 , wherein R 6 is H.
8 . The pharmaceutical composition of claim 1 , wherein Y is O.
9 . The pharmaceutical composition of claim 1 , wherein the A in the ortho position relative to R 1 is H.
10 . The pharmaceutical composition of claim 1 , wherein the SOX9 dimerization inhibitor is a compound selected from the group consisting of
11 . The pharmaceutical composition of claim 1 for use in treating a disease or condition characterized by increased dimeric SOX9 activity and/or increased CSPG expression, or a disease or disorder that may be ameliorated by decreasing dimeric SOX9 or CSPG activity.
12 . The pharmaceutical composition of claim 11 , wherein the disease or condition is a condition involving inhibited neuronal growth or neuronal plasticity, fibrotic disorders and cancer.
13 . A SOX9 dimerization inhibitor that is:
a compound of formula I:
where:
R 1 is NR 7 R 8 , wherein R 7 and R 8 are each independently a straight or branched C 1 to C 6 alkyl, or R 7 and R 8 , together with the N atom to which they are attached, form a heterocyclyl containing one or two heteroatoms selected from N and O, which is optionally substituted with an alkyl;
R 2 is H, a C 1 to C 6 alkyl, a C 1 to C 6 alkoxy, or halo; and
one A is H and the other is:
where:
R 3 is H or a C 2 to C 6 alkyl;
R 4 is H or a C 1 to C 6 alkyl;
R 5 is H, halo or NCH 2 C 6 H 5 ;
R 6 is H or methyl; and
Y is O or SO 2 ,
or a pharmaceutically acceptable salt or solvate thereof, with the proviso that the compound is not
and wherein
when:
R 2 , R 3 , R 4 , R 5 and R 6 are H and Y is O, then R 1 is not 4-methylpiperazyn-1-yl, morpholino, or pyrrol-1-yl;
R 2 is H or OCH 3 , R 3 , R 5 and R 6 are H, R 4 is CH 3 and Y is O, then R 1 is not piperidin-1-yl;
R 2 , R 5 and R 6 are H, R 3 is isopropyl and R 4 is CH 3 and Y is O, then R 1 is not piperidin-1-yl, morpholino; and
R 5 and R 6 are H, R 3 is isopropyl and R 2 and R 4 are CH 3 and Y is O, then R 1 is not —N(CH 2 CH 3 ) 2 .